Genetic Variant NFE2L2:c.184-31038A>C (chr2-177265309-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000464747.5(NFE2L2):c.-3-31038A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.878 in 213,946 control chromosomes in the GnomAD database, including 82,704 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.88 ( 59765 hom., cov: 34)

Exomes 𝑓: 0.86 ( 22939 hom. )

Consequence

NFE2L2
ENST00000464747.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.221

Publications

169 publications found

Variant links:

Genes affected

NFE2L2 (HGNC:7782): (NFE2 like bZIP transcription factor 2) This gene encodes a transcription factor which is a member of a small family of basic leucine zipper (bZIP) proteins. The encoded transcription factor regulates genes which contain antioxidant response elements (ARE) in their promoters; many of these genes encode proteins involved in response to injury and inflammation which includes the production of free radicals. Multiple transcript variants encoding different isoforms have been characterized for this gene. [provided by RefSeq, Sep 2015]

NFE2L2 Gene-Disease associations (from GenCC):

immunodeficiency, developmental delay, and hypohomocysteinemia
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Illumina, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

NFE2L2 links:

ENSG00000222043 (HGNC:):

ENSG00000222043 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000464747.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NFE2L2	ENST00000699346.1		c.184-31038A>C	intron	N/A	ENSP00000514321.1	A0A8V8TNM0
NFE2L2	ENST00000586532.6	TSL:5	c.43-31038A>C	intron	N/A	ENSP00000464920.2	K7EIW5
NFE2L2	ENST00000699265.1		c.43-31038A>C	intron	N/A	ENSP00000514246.1	K7EIW5

Frequencies

GnomAD3 genomes

AF:

0.884

AC:

134590

AN:

152168

Hom.:

59705

Cov.:

show subpopulations

Gnomad AFR

AF:

0.929

Gnomad AMI

AF:

0.895

Gnomad AMR

AF:

0.857

Gnomad ASJ

AF:

0.877

Gnomad EAS

AF:

0.730

Gnomad SAS

AF:

0.845

Gnomad FIN

AF:

0.848

Gnomad MID

AF:

0.870

Gnomad NFE

AF:

0.884

Gnomad OTH

AF:

0.891

GnomAD4 exome

AF:

0.861

AC:

53083

AN:

61660

Hom.:

22939

Cov.:

AF XY:

0.862

AC XY:

24836

AN XY:

28822

show subpopulations

African (AFR)

AF:

0.932

AC:

2478

AN:

2660

American (AMR)

AF:

0.854

AC:

1521

AN:

1782

Ashkenazi Jewish (ASJ)

AF:

0.879

AC:

3362

AN:

3826

East Asian (EAS)

AF:

0.728

AC:

6837

AN:

9396

South Asian (SAS)

AF:

0.862

AC:

486

AN:

564

European-Finnish (FIN)

AF:

0.862

AC:

150

AN:

174

Middle Eastern (MID)

AF:

0.872

AC:

321

AN:

368

European-Non Finnish (NFE)

AF:

0.884

AC:

33440

AN:

37826

Other (OTH)

AF:

0.886

AC:

4488

AN:

5064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

360

721

1081

1442

1802

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.885

AC:

134704

AN:

152286

Hom.:

59765

Cov.:

AF XY:

0.881

AC XY:

65607

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.929

AC:

38625

AN:

41568

American (AMR)

AF:

0.857

AC:

13120

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.877

AC:

3045

AN:

3472

East Asian (EAS)

AF:

0.730

AC:

3762

AN:

5154

South Asian (SAS)

AF:

0.845

AC:

4081

AN:

4830

European-Finnish (FIN)

AF:

0.848

AC:

8998

AN:

10612

Middle Eastern (MID)

AF:

0.878

AC:

258

AN:

294

European-Non Finnish (NFE)

AF:

0.884

AC:

60114

AN:

68028

Other (OTH)

AF:

0.893

AC:

1885

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

837

1673

2510

3346

4183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

900

1800

2700

3600

4500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.888

Hom.:

33845

Bravo

AF:

0.886

Asia WGS

AF:

0.820

AC:

2853

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

8.4

(source)

DANN

Benign

0.64

PhyloP100

0.22

PromoterAI

0.022

Neutral

(source)

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over